Type 1 Gaucher disease (GDI) is the most common form of the disorder with an incidence of 1 in 50,000 births. The underlying problem is accumulation of glucocerebroside due to a lysosomal enzyme deficiency, which may cause oxidative stress and inflammation contributing to the onset of symptoms. Standard texts state that GDI does not involve the brain. This view is now being challenged based on imaging, postmortem, and clinical studies. For example, individuals with GDI have an elevated risk of Parkinson's disease, indicating brain involvement. Current therapies significantly improved outcomes, but do not completely return glucocerebroside levels to the normal range nor completely resolve symptoms or prevent continuing tissue injury. Thus, additional treatments that target oxidative stress and inflammation have the potential to ameliorate both systemic and brain symptoms and may alter disease progression. Our central hypothesis is that relative to healthy subjects, GDI patients exhibit increased systemic and brain oxidative stress and inflammation. Further, we hypothesize that antioxidant/anti-inflammatory therapy can improve oxidative stress/inflammation in GDI patients. We propose the following aims to test these hypotheses. In Aim 1 we will compare in GDI patients and healthy subjects oxidative stress and inflammatory markers in plasma and blood using bioanalytical methods and in brains using magnetic resonance spectroscopy. In Aim 2 we will study GDI patients to: a) determine if oral N-acetylcysteine (NAC) improves plasma, blood and brain measures of oxidative stress and inflammation; b) evaluate correlations between plasma/blood NAC, cysteine, and glutathione (GSH) concentrations with brain GSH levels; and c) characterize NAC and GSH pharmacokinetics using validated bioanalytical methods and construct models linking pharmacokinetics with biomarkers. Impact: our results will lead to a greater understanding of GDI pathophysiology; identify potential biomarkers for use in diagnosis, monitoring disease progression, and therapy; provide information needed to determine if phase III clinical trials of NAC or other antioxidants/anti-inflammatories are warranted; and guide study design and sample size estimation.